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Anthracyclines

Anthracyclines are anticancer compounds that were originally derived fromStreptomycesand their

anti-tumor activities were established in the 1960s[1]. Anthracyclines are red aromatic polyketidesand occur in variety of forms due to the structural differences in the aglycone and the different

sugar residues attached[2].

Major Drugs in the class

Daunorubicin

Daunomycin (daunorubicin) was the first anthracycline compound to be chatacterized structurally

and stereochemically. Danorubicin is used in treating acute lymphoblastic and myeloblastic

leukaemias.

Doxorubicin

Adriamycin (generic name doxorubicin) is a hydroxyl derivative of daunorubicin is [3, 4].

Doxorubicin is one of the most widely used chemotherapeutic agents and is generally prescribed incombination with other drugs.Doxorubicin has a broad spectrum of activity. It is one of the most

effective drugs for solid tumor treatment, e.g., breast cancer, small cell lung cancer and ovarian

carcinoma treatments. It has significant activity against bladder, stomach, liver and thyroid tumors,Ewings and osteogenic bone tumors, soft tissue sarcoma, neuroblastoma and Wilms tumor. It is also

active against multiple myeloma, several types of leukaemia and cutaeneous T-cell lymphoma. It is

also plays an important role in treatment of Hodgkins disease and non-Hodgkins lymphomas[5].

Due to development of resistance in the tumor cells to daunorubicin and doxorubicin, dose

dependent cardiotoxicity, and several other side-effects, modification of these drugs to produce

analogs with wider activity and lower toxicity have been sought. Efforts to find better

anthracyclines and over the years the number of analogs have risen to more than 2000 [6]. However,

only very few anthracycline analogs like epirubicin and idarubicin[7] have been approved for clinical

use.

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Epirubicin

Epirubicin is an epimer of doxorubicin and differs only in the orientation of the C-4 hydroxyl group

on the sugar. Because of this slight change in the structure, epirubicin has lower cardiotoxicity thandoxorubicin. Epirubicin is used in the treatment of gastric and breast cancer and is also indicated

for the treatment of carcinoid, endometrial, lung, ovarian, esophageal and prostate cancers as well

as soft tissue sarcomas [5].

Idarubicin

Idarubicin is an analog of daunorubicin. It lacks the C-4 methoxy group and this increases its

lipophilicity. Idarubicin has improved activity as induction therapy for acute myelogenous

leukaemia[5].

Valrubicin

Valrubicin is N-trifluoroacetyl, 1-4-valerate derivative of doxorubicin. Valrubicins enters cells more

rapidly than doxorubicin. It is used specifically in the treatment of early bladder cancer [8].

Mechanism of action

The mechanism by which anthracyclines inhibit cancer is still not completely clear and multiple

pathways are thought to be involved in the cytotoxicity of this class of anti-cancer drugs. The useful

pathways are the ones that are actually involved in toxicity to the neoplasia while not being toxic to

the organism.

Accumulation of anthracyclines in the nucleus of neoplastic and proliferating cells

Anthracyclines enter the cells through passive diffusion[9]. An elegant mechanism of the selective

transport of anthracyclines to the nuclei of neoplastic and proliferating cells has been proposed by

Kiyomiya and colleagues[10, 11]. It has been demonstrated with doxorubicin that once it enters the

cells, it binds the proteasomes in the cytoplasm for which it has high affinity. The drug-proteasome

complex is then translocated into the nucleus. Proteasomes are shown to be located predominantly

in the nucleus of neoplastic and normal proliferative cells as compared to the non-proliferative

normal cells that show the presence of proteasomes predominantly in the cytoplasm[12-14]. Thus

there will be a relatively higher transport of anthracyclines into the nucleus of the neoplastic and

non-differentiated, proliferative normal cells. Once the anthracyclines reach the nucleus they would

dissociate from the proteasome and bind DNA due to its higher affinity for DNA. This would bringabout the DNA mediated effects of anthracyclines. Moreover, binding of anthracyclines to

proteasomes also inhibits the protease activity leading to inhibition of degradation of proteins

involved in cell growth and metabolism and thus inducing apoptosis of these cells.

DNA intercalation

Intercalation into DNA leading to inhibition of macromolecular synthesis was the first mechanism

described for cytotoxicity of anthracyclines[15]. The rather strong binding of daunorubicin and

doxorubicin to DNA has been characterized extensively [16-18]. However, it has been seen with other

anthracyclines like those of the nogalamycin family that the antitumor activity correlates with a

decrease in affinity for DNA [19, 20]. Considering this and also taking into account that the DNA in

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cells does not occur naked but as chromatin, it seems unlikely that DNA intercalation is the only or

most essential pathway of anthracycline cytotoxicity.

On the other hand, anthracyclines like doxorubicin at low concentrations have been shown toselectively displace nuclear proteins[21], and daunorubicin has been shown to induce aggregation of

chromatin[22]. The proposed mechanism involves initial intercalation of the drug into the linker

regions where the DNA is free of nuclear proteins, leading to conformational changes in DNA that

extend towards the histone octamer and result in the unfolding of chromatin and its subsequent

aggregation[22].

Interaction with DNA binding proteins

Regulation of gene expression by inhibiting, or promoting, the binding of transcription factors is

also considered to play a role in anthracycline cytotoxicity with the potential involvement of SP-1

transcription factor as a specific target for these drugs [23, 24]. Involvement of anthracyclines in

inhibiting DNA synthesis by affecting the initiation or the elongation phase, and RNA synthesis by

inhibiting RNA polymerase activity has also been documented[25-27]. Another mechanism that hasgained ground is the anthracycline activity as Topoisomerase II poisons[28]. After DNA intercalation,

anthracycline rings that do not intercalate into the DNA seem to play a role in stabilizing the

complex between Topoisomerase II and the DNA that it has nicked. The DNA nicks cannot be sealed

and this leads to an accumulation of DNA damage that is cytotoxic due to growth arrest in G1 and

G2 and programmed cell death[29]. Doxorubicin and Idarubicin have also been showed to inhibit

Topoisomerase I and this is proposed to be an ancillary mechanism of cytotoxic activity of

anthracyclines[30].

Anthracyclines, p53 and apoptosis

Like any other genotoxic agent, doxorubicin has been demonstrated to induce the binding of p53 to

DNA. As p53 is a major player in some forms of apoptosis, it has been proposed that anthracyclines

may exert their cytotoxic effect via p53 mediated apoptosis. There are contradictory reports

regarding this link between anthracyclines, p53 and apoptosis[29, 31, 32]. It is observed that there are

more DNA breaks in p53 proficient cells than in p53 deficient cells although the levels ofTopoisomerase II are same in the two cell types. It is therefore also proposed that p53 exerts this

activity by binding to Topoisomerase II and inhibiting its ligase activity [33, 34]. However, clinical

concentrations of these drugs induce apoptosis pathways that do not always require p53 by

triggering a cyclic cascade of sphingomyelin hydrolysis and formation of ceramide [35]. It is also

observed that anthracyclines can release cytochrome C from mitochondria directly and induce

apoptosis[36]. Thus, although p53 seems to play some role in the activity of anthracyclines, it is not

necessarily the only mechanism.

Free radical generation

One electron addition to the quinone moiety in ring C of anthracyclines leads to formation of

semiquinone that regenerates back to quinone by reducing oxygen to reactive oxygen species like

superoxide anion and hydrogen peroxide. The semiquinone can oxidize with the bond between ring

A and daunosamine which results in deglycosylation. The aglycone thus formed has higher

solubility in lipids and can intercalate into biological membranes and form reactive oxygen species

which can affect sensitive targets[37, 38]. The one electron redox cycle of doxorubicin has beendemonstrated to induce the release of iron from the stores. Doxorubicin forms complex with iron

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and this complex is capable of producing hydroxyl ions which is a more potent reactive oxygen

species[39, 40]. Thus, there seems to be involvement of oxidative damage in the mechanism of

anthracycline activity. However, as the production of measurable reactive oxygen species is

predominantly observed at supraclinical concentrations, this may not be the direct mechanism ofanthracycline activity. Reactive oxygen species though can act as signaling molecules at very low,

unmeasurable concentrations and induce apoptosis and this could be one of the mechanism by

which anthracyclines exert their cytotoxic effect.

Antiangiogenic mechanism

A recent study[ shows that the anthracyclines inhibit transcriptional factor HIF-1 from binding to

DNA in hypoxic human cells and inhibited tumor growth in human prostate cancer xenografts.

Inhibition of HIF-1 transcriptional activity leads to decreased VEGF, SDF1 and SCF expression

because of which there is decreased CAC mobilization and this results in decreased tumor

vascularization and growth. Thus, anthracyclines can also inhibit cell growth through

antiangiogenic pathways.

Side Effects

The side effects of anthracyclines, like any other chemotherapeutic agent, are linked to their

cytotoxicity to non-differentiated, proliferating normal cells. These side effects include nausea,

vomiting, and alopecia. However, the major toxicities of anthracyclines include cardiotoxicity and

myelosuppression and these are the major limitations of these drugs. Doxorubicin can also causesevere local tissue necrosis. Cardiomyopathy and congestive heart failure are the two cardiotoxic

side effects of anthracyclines. Epirubicin is less cardiotoxic than doxorubicin but may not totally

eliminate the risk of chronic cardiotoxicity[5].

Anthracycline induced cardiotoxicity is irreversible and is thus an especially important

consideration in treatment of curative malignancies in pediatric patients[4. As discussed in the

mechanism of action of anthracyclines, the interaction between anthracyclines and iron[ is found to

play a role in anthracycline induced cardiomyopathies by producing potent reactive oxygen species.

An iron chelator dexrazoxane has now been approved for use in patients who are prescribed high

doses of doxorubicin to prevent cardiotoxicity.

Various other strategies to prevent the cardiotoxicity of anthracyclines are also being employed

that include change in administration of the drugs, limiting the overall dosage, encapsulation into

liposomes, combination treatment, use of cardioprotectors and synthesis of modified

anthracyclines[5].

Allergic reactions

Although rare, mild to medium allergic reactions have been reported for anthracyclines. The

symptoms include generalized urticaral exanthema as reported for epirubicin and doxorubicin.High doses of epirubicin can cause high fever, hypertension and hypoxia as hypersensitivity

symptoms. Pegylated and liposomal doxorubicine and daunorubicin that have lower toxicity have

been reported to produce acute hypersensitivity infusion reactions.